The present invention relates generally to a series of novel small molecules, their synthesis and their use in the treatment of inflammatory disease.
Research spanning the last decade has helped to elucidate the molecular events attending cell-cell interactions in the body, especially those events involved in the movement and activation of cells in the immune system. See generally, Springer, T. Nature, 1990, 346, 425-434. Cell surface proteins, and especially the Cellular Adhesion Molecules (xe2x80x9cCAMsxe2x80x9d) and xe2x80x9cLeukointegrinsxe2x80x9d, including LFA-1, MAC-1 and gp 150.95 (referred to in WHO nomenclature as CD18/CD11 a, CD18/CD 11b, and CD18/CD11c, respectively) have correspondingly been the subject of pharmaceutical research and development having as its goal the intervention in the processes of leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory component of the inflammatory response, activation of integrins constitutively expressed on leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g., LFA-1) and one or several distinct intercellular adhesion molecules (ICAMs) designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vessel endothelial cell surfaces and on other leukocytes. The interaction of the CAMs with the Leukointegrins is a vital step in the normal functioning of the immune system. Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally Kishimoto, T. K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.
A group of individuals has been identified which lack the appropriate expression of Leukointegrins, a condition termed xe2x80x9cLeukocyte Adhesion Deficiencyxe2x80x9d (Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD18 family. By virtue of the fact that LAD patients who lack CD18 cannot mount an inflammatory response, it is believed that antagonism of CD18, CD11/ICAM interactions will also inhibit an inflammatory response.
It has been demonstrated that the antagonism of the interaction between the CAMs and the Leukointegrins can be realized by agents directed against either component. Specifically, blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1, by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune response inhibited by antibodies to CAMs or Leukointegrins include antigen or mitogen-induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. The relevance of the in vitro studies are supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice (Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greater significance, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J Immunol. 1990, 144, 4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37, 992-1004) and antibodies directed against LFA-1 have demonstrated immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A.; et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation, 1991, 52, 291-295).
It has also been demonstrated that a recombinant soluble form of ICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18,CD11/ICAM-1 interactions on cells and shows inhibitory activity in in vitro models of immune response such as the human mixed lymphocyte response, cytotoxic T cell responses and T cell proliferation from diabetic patients in response to islet cells (Becker, J. C.; et al, J. Immunol. 1993, 151, 7224 and Roep, B. O.; et al., Lancet, 1994, 343, 1590).
Thus, the prior art has demonstrated that large protein molecules which antagonize the binding of the CAMs to the Leukointegrins have therapeutic potential in mitigating inflammatory and immunological responses often associated with the pathogenesis of many autoimmune or inflammatory diseases. However proteins have significant deficiencies as therapeutic agents, including the inability to be delivered orally and potential immunoreactivity which limits the utility of theses molecules for chronic administration. Furthermore, protein-based therapeutics are generally expensive to produce.
Several small molecules have been described in the literature which affect the interaction of CAMs and Leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be inhibitory in an in vitro cell binding assay (Musza, L. L.; et al., Tetrahedron, 1994, 50, 11369-11378). One series of molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in a reverse passive Arthus reaction, an induced model of inflammation that is characterized by neutrophil accumulation (Chang, Y. H.; et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another series of molecules was also found to be orally active in a delayed type hypersensitivity reaction in rats (Sanfilippo, P. J.; et al., J. Med. Chem. 1995, 38, 1057-1059). All of these molecules appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other proteins or act intracellularly to inhibit the activation of the Leukointegrins by an unknown mechanism. None of the molecules directly antagonize the interaction of the CAMs with the Leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules are not likely to be satisfactory for therapeutic use.
It follows that small molecules having the similar ability as large protein molecules to directly and selectively antagonize the binding of the CAMs to the Leukointegrins would make preferable therapeutic agents. WO9839303 discloses a class of small molecule inhibitors of the interaction of LFA-1 and ICAM-1. WO9911258 discloses that the fungal metabolite mevinolin and derivatives bind to LFA-1 and disrupt the interaction of LFA-1 and ICAM-1.
A first aspect of the invention comprises a method for treating or preventing inflammatory and immune cell-mediated diseases by the administration of certain novel small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a). A second aspect of the invention comprises novel small molecules having the above-noted therapeutic activities. A third aspect of the invention comprises methods for making these novel compounds. A final aspect of the invention comprises pharmaceutical compositions comprising the above-mentioned compounds suitable for the prevention or treatment of inflammatory and immune cell-mediated conditions.
The invention comprises compounds of the formula I: 
wherein:
A1, A2 and A3 are each, independently, xe2x95x90Nxe2x80x94 or xe2x95x90CHxe2x80x94;
D is xe2x95x90Nxe2x80x94, xe2x95x90CR1xe2x80x94, xe2x95x90CSO2R1xe2x80x94, xe2x95x90CSOR1xe2x80x94, xe2x95x90CSR1xe2x80x94, xe2x95x90COR1xe2x80x94, xe2x95x90CCOR1xe2x80x94, or xe2x95x90CNHR1xe2x80x94,
wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) halogen,
(ii) oxo,
(iii) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula: 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) cyano,
(vi) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(viii) a group of the formula xe2x80x94SR22, wherein R22 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) a quaternary group of the formula: 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula: 
wherein r is 2, 3, 4, 5 or 6, and
R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula: 
wherein s is 2, 3, 4, 5 or 6, and
R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano, or
(xi) an amidino group of the formula: 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(I) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(J) a morpholinyl moiety, or,
(K) halogen;
X is an oxygen or sulfur atom;
R3 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(ii) a group of the formula xe2x80x94NR49R50, wherein R49 and R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms;
R4 is a group of the formula xe2x80x94(CR51R52)x(CR53R54)yR55, wherein;
x and y are each independently 0 or 1,
R51, R52 and R53 are each, independently:
(A) a hydrogen atom,
(B) a group of the formula xe2x80x94OR56, wherein R56 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
R54 is:
(A) a group of the formula R57, wherein R57 is defined similarly to R1 above, or
(B) a group of the formula xe2x80x94OR58, wherein R58 is defined similarly to R1 above;
R55 is:
aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b] furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) a group of the formula xe2x80x94COOR60, wherein R60 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(iii) a group of the formula xe2x80x94NR61R62, wherein R61 and R62 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R61 and R62 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94CONR63R64, wherein R63 and R64 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R63 and R64 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(v) a group of the formula xe2x80x94OR65, wherein R65 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vi) a group of the formula xe2x80x94SR66, wherein R66 is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vii) cyano,
(viii) nitro, or
(ix) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R59,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR68R69, wherein R68 and R69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R68 and R69 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R68 and R69 may additionally be the group R59,
(F) a group of the formula xe2x80x94CONR70R71, wherein R70 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R70 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R70 and R71 may additionally be the group R59,
(G) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(H) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(I) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(J) cyano,
(K) nitro, or
(L) halogen;
R5 is Cl or trifluoromethyl;
Z is xe2x95x90Nxe2x80x94 or xe2x95x90CR6xe2x80x94 wherein R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when Z is N or xe2x95x90CHxe2x80x94, R7 is chlorine or trufluoromethyl;
and pharmaceutically acceptable salts thereof
As the term is used herein, a xe2x80x9cpharmaceutically acceptable counter ionxe2x80x9d is any counter ion generally regarded by those skilled in the pharmaceutical art as being pharmaceutically acceptable. For a discussion of what are pharmaceutically acceptable counter ions, reference may be had to Stephen M. Bergle, Lyle D. Bighley and Donald C. Monkhouse, xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Sciences, 66 (1977), 1-19. By way of non-limiting example, the chloride, bromide, acetate, and sulphate ions are pharmaceutically acceptable counter ions.
Preferred compounds of the invention are those of formula I as given above wherein:
A1, A2 and A3 are each, independently, xe2x95x90Nxe2x80x94 or xe2x95x90CHxe2x80x94;
D is xe2x95x90Nxe2x80x94, xe2x95x90CR1xe2x80x94, xe2x95x90CSO2R1xe2x80x94, xe2x95x90CSOR1xe2x80x94, xe2x95x90CSR1xe2x80x94, xe2x95x90COR1xe2x80x94, xe2x95x90CCOR1xe2x80x94, or xe2x95x90CNHR1xe2x80x94,
wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) halogen,
(ii) oxo,
(iii) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R1 1 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula: 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) cyano,
(vi) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(viii) a group of the formula xe2x80x94SR22, wherein R22 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(x) a quaternary group of the formula: 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula: 
wherein r is 2, 3, 4, 5 or 6, and
R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula: 
wherein s is 2, 3, 4, 5 or 6, and
R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano, or
(xi) an amidino group of the formula: 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(I) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(J) a morpholinyl moiety, or,
(K) halogen;
X is an oxygen or sulfur atom;
R3 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(ii) a group of the formula xe2x80x94NR49R50, wherein R49 and R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein:
R55 is:
aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b] furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) cyano,
(iii) nitro, or
(iv) halogen,
(B) methyl, which may be mono- or polysubstituted with fluorine atoms and additionally may be monosubstituted with R59,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR68R69, wherein R68 and R69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R68 and R69 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R68 and R69 may additionally be the group R59,
(F) a group of the formula CONR70R71, wherein R70 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R70 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R70 and R71 may additionally be the group R59,
(G) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(H) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(I) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(J) cyano,
(K) nitro, or
(L) halogen;
R5 is Cl or trifluoromethyl;
Z is xe2x95x90Nxe2x80x94 or xe2x95x90CR6xe2x80x94 wherein R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when Z is N or xe2x95x90CHxe2x80x94, R7 is chlorine or trufluoromethyl;
and pharmaceutically acceptable salts thereof.
More preferred compounds of the invention are those of the formula I, wherein:
A1, A2 and A3 are each, independently, xe2x95x90Nxe2x80x94 or xe2x95x90CHxe2x80x94;
D is xe2x95x90Nxe2x80x94, xe2x95x90CR1xe2x80x94, xe2x95x90COR1xe2x80x94, xe2x95x90CCOR1xe2x80x94, or xe2x95x90CSO2R1xe2x80x94,
wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) oxo,
(ii) phenyl, wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11 R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula: 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iv) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(v) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(vi) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(vii) a quaternary group of the formula: 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula: 
wherein r is 2, 3, 4, 5 or 6, and
R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula: 
wherein s is 2, 3, 4, 5 or 6, and
R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) phenyl, wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano, or
(xi) an amidino group of the formula: 
wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(I) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(J) a morpholinyl moiety, or,
(K) halogen;
X is an oxygen atom;
R3 is:
(A) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein;
R55 is:
phenyl, wherein one or more of the hydrogen atoms at the 3 and 4 positions of said phenyl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 2-, 3- or 4-pyridyl, or 2-, 4- or 5-pyrimidinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) cyano,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(G) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(H) cyano,
(I) nitro, or
(J) halogen;
R5 is Cl;
Z is xe2x95x90CHxe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Even more preferred compounds are those of the formula I, wherein:
A1, A2 and A3 are each xe2x95x90CHxe2x80x94;
D is xe2x95x90CR1xe2x80x94, xe2x95x90COR1xe2x80x94, xe2x95x90CCOR1xe2x80x94, or xe2x95x90CSO2R1xe2x80x94,
wherein R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) oxo,
(ii) phenyl, wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R 10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano, or
(k) an amidino group of the formula: 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(iii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iv) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(v) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(vi) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(vii) a quaternary group of the formula: 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula: 
wherein r is 2, 3, 4, 5 or 6, and
R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula: 
wherein s is 2, 3, 4, 5 or 6, and
R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) phenyl,
wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano, or
(xi) an amidino group of the formula: 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(I) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(J) a morpholinyl moiety, or,
(K) halogen;
X is an oxygen atom;
R3 is:
(A) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein;
R55 is:
phenyl, wherein one or more of the hydrogen atoms at the 3 and 4 positions of said phenyl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 2-, 3- or 4-pyridyl, or 2-, 4- or 5-pyrimidinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) cyano,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(G) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(H) cyano,
(I) nitro, or
(J) halogen;
R5 is Cl;
Z is xe2x95x90CHxe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Further preferred compounds of the invention are those of the formula I,
wherein:
A1, A2 and A3 are each xe2x95x90CHxe2x80x94;
D is =CCOR1xe2x80x94 or xe2x95x90CSO2R1xe2x80x94,
R1 is:
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(i) oxo,
(ii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iii) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2, or
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(vi) a quaternary group of the formula: 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(C) a branched or unbranched carboxylic acid group of 3 to 6 carbon atoms,
(D) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(F) an amidino group of the formula: 
wherein r is 2, 3, 4, 5 or 6, and
R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) an guanidino group of the formula: 
wherein s is 2, 3, 4, 5 or 6, and
R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(I) a morpholinyl moiety, or,
(J) halogen;
X is an oxygen atom;
R3 is:
(A) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein;
R55 is:
phenyl, wherein one or more of the hydrogen atoms at the 3 and 4 positions of said phenyl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 2-, 3- or 4-pyridyl, or 2-, 4- or 5-pyrimidinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(ii) cyano,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(G) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(H) cyano,
(I) nitro, or
(J) halogen;
R5 is Cl;
Z is xe2x95x90CHxe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof
Especially preferred compounds of the invention are those of the formula I
wherein:
A1, A2 and A3 are each xe2x95x90CHxe2x80x94;
D is xe2x95x90CCOR1xe2x80x94 or xe2x95x90CSO2R1xe2x80x94,
R1 is
(A) a hydrogen atom,
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(C) a group of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(D) a morpholinyl moiety;
X is an oxygen atom;
R3 is methyl;
R4 is a group of the formula xe2x80x94CH2R55, wherein;
R55 is:
phenyl, wherein one or more of the hydrogen atoms at the 4 position of said phenyl group may be optionally and independently replaced with:
(A) R59, which is aryl selected from the class consisting of phenyl, 3-pyridyl, or 5-pyrimidinyl, wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) methyl,
(ii) cyano,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) cyano,
(D) nitro, or
(E) halogen;
R5 is Cl;
Z is xe2x95x90CHxe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
The following are representative compounds of the invention:
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,3-dihydro-indol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-3-methyl-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-4-hydroxy-3-methyl-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-5-fluoro-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-1,3-dihydroindol-2-one-6-carboxylic acid
3-benzyl-1-(3,5-dichlorophenyl)-4-methoxy-1,3-dihydroindol-2-one
3-(3-bromobenzyl)-1-(3,5-dichlorophenyl)-4-methoxy-1,3-dihydroindol-2-one
3-(3-bromobenzyl)-1-(3,5-dichlorophenyl)-4-hydroxy-3-methyl-1,3-dihydroindol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-4-hydroxy-1,3-dihydroindol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-5-methoxy-1,3-dihydroindol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-5-hydroxy-1,3-dihydroindol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-1,3-dihydroindol-2-one
3-benzyl-1-(3,5-dichlorophenyl)-4-hydroxy-3-methyl-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-4-hydroxy-1,3-dihydroindol-2-one
3-(4-bromobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one
3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one
It will be appreciated that the compounds of the formula I have at least one chiral center. Ultimately preferred are those compounds of formula I with the absolute stereochemistry depicted below in formula Ia: 
Compounds of the invention may be prepared by the general method described below. Typically, reaction progress may be monitored by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature. 
As illustrated in Scheme I, intermediate II undergoes Ullman coupling with aryl bromide III in the presence of copper and a base such as potassium carbonate in a suitable solvent such as 1,2-dichlorobenzene, preferably at the reflux temperature of the solvent. A catalytic amount of copper iodide may optionally be added. The product IV is reacted with a suitable chlorinating agent such as N-chlorosuccinimide in a suitable solvent such as acetic acid at a temperature from about room temperature to the reflux temperature of the solvent, preferably the reflux temperature. The intermediate chloro compound is then hydrolyzed, for example by diluting the cooled reaction mixture with an aqueous acid such as 70% aqueous phosphoric acid, and heating, preferably at reflux temperature, to provide V.
Intermediate V is condensed with aldehyde RACHO (the appropriate R4 precursor) in a suitable solvent such as MeOH, in the presence of a base catalyst such as piperidine, preferably at the reflux temperature of the solvent to provide olefin VI. The olefin is reduced in a suitable solvent such as MeOH-acetic acid under preferably about 30 to 60 psi of hydrogen gas, in the presence of a suitable catalyst, such as 5% palladium sulfide on carbon. An additional solvent, such as dichloromethane may be added to improve solubility of the starting material (VI). The reduction product I (R3=H) may then be alkylated by treating it with a base, such as potassium (trimethylsilyl)amide in a suitable solvent, such as DMF at a temperature of about 0 to xe2x88x9278xc2x0 C. and preferably about xe2x88x9220 to xe2x88x9240xc2x0 C., followed by quenching of the resulting anion with the desired alkyl halide (R3X) to provide I (R3 is alkyl or substituted alkyl).
An alternate method for preparing compounds of formula I, where A1=N is illustrated in Scheme II, and described generally in the chemical literature (P. C. Ting et al., J. Med. Chem., 1990, 33, 2697). 
2-Chloronicotinic acid and VII are combined in a suitable solvent such as acetic acid and heated, preferably at reflux temperature for about 2-6 hr to provide VIII. This is treated with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as THF, preferably at reflux temperature, to provide IX. Treatment of IX with a suitable chlorinating agent, such as thionyl chloride provides X.
Treatment of X with thiophenol in the presence of a base, such as NaOH, in a suitable solvent, such as ethanol/water, provides thioether XI. Treatment of XI with a strong base, such as n-BuLi in a suitable solvent, such as THF, at about xe2x88x9230 to xe2x88x9278xc2x0 C. followed by reaction with carbon dioxide and treatment of the resulting intermediate with an acid, such as trifluoroacetic acid, in a suitable co-solvent such as methylene chloride provides XII. Treatment of XII with a halide, preferably an iodide or bromide, R3X, in the presence of a base, such as sodium hydride, in a suitable solvent such as THF at about 0xc2x0 C. to ambient temperature, provides XIII. Desulfurization of XIII, for example with zinc dust and trimethylsilyl chloride in a suitable solvent, such as THF with water, provides XIV. XIV may then be treated with another halide, preferably iodide or bromide, R4X, in the presence of a base, such as sodium hydride, in a suitable solvent such as THF at about 0xc2x0 C. to ambient temperature, to provide I (A1=N)